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Utökad övervakningMiljöinformationReceptstatusFörmånsstatus
Sanofi AB

Filmdragerad tablett 100 mg
(rund, bikonvex, vit, filmdragerad, märkt "Z100" på ena sidan)

Proteinkinashämmare, övriga cytostatiska, cytotoxiska medel

Aktiv substans:
ATC-kod: L01XE12
Läkemedel från Sanofi AB omfattas av Läkemedelsförsäkringen.
  • Vad är miljöinformation?

Miljöpåverkan (Läs mer om miljöpåverkan)

Vandetanib

Miljörisk: Användning av vandetanib har bedömts medföra försumbar risk för miljöpåverkan.
Nedbrytning: Vandetanib är potentiellt persistent.
Bioackumulering: Vandetanib har låg potential att bioackumuleras.


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Detaljerad miljöinformation


PEC/PNEC = 0.000061 μg/L / 1.0 μg/L = 0.000061

PEC/PNEC < 0.1


Environmental Risk Classification


Predicted Environmental Concentration (PEC)


The PEC is based on following data:


PEC (µg/L) = (A*109*(100-R))/(365*P*V*D*100)


PEC (µg/L) = 1.5*10-6*A*(100-R)


A (kg/year) = total sold amount API in Sweden year 2015, data from IMS Health.

R (%) = removal rate (due to loss by adsorption to sludge particles, by volatilization, hydrolysis or biodegradation) = 0.

P = number of inhabitants in Sweden = 9 *106

V (L/day) = volume of wastewater per capita and day = 200 (ECHA default)(Ref 1)

D = factor for dilution of waste water by surface water flow = 10 (ECHA default)(Ref 1)

(Note: The factor 109 converts the quantity used from kg to μg).


A = 0.4080 kg


R = 0


PEC = 1.5 * 10-6 * 0.4080 * (100-0) = 0.000061μg/L


(Note: Whilst vandetanib is metabolised in humans, little is known about the ecotoxicity of the metabolites. Hence, as a worst case, for the purpose of this calculation, it is assumed that 100% of excreted metabolites have the same ecotoxicity as parent vandetanib).


Metabolism

After oral administration 69% of vandetanib was excreted either as parent compound or metabolites. Approximately 44 % was excreted via faeces and 25 % via urine (Ref2).



Ecotoxicity Data

Endpoint

Species

Common Name

Method

Time

Result

Reference

EC50 - Based on Growth Rate

Pseudo-kirchneriella subcapitata

Green Algae

OECD 201

72 h

0.30 mg/L

Note 1

3

NOEC - Based on Growth Rate

0.11 mg/L

Note 1

EC50 - Based on Immobilisation

Daphnia magna

Giant Water Flea

OECD 202

48 h

2.6 mg/L

Note 4

4

NOEC - Based on Immobilisation

0.10 mg/L

Note 4

EC50 - Based on Reproduction & Length

Daphnia magna

Giant Water Flea

OECD 211

21 d

>0.61 mg/L

Note 1

5

NOEC - Based on Reproduction & Length

0.30 mg/L

Note 1

LOEC - Based on Reproduction & Length

0.61 mg/L

Note 1

NOEC - Based on Overall Endpoints

Note 5

Chironomus riparius

Midge

OECD 218

28 d

100 mg/kg sediment (dry weight)

Note 3

6

LOEC - Based on Overall Endpoints

Note 5

100 mg/kg sediment (dry weight)

Note 3

LC50

Oncorhynchus mykiss

Rainbow Trout

OECD 203

96 h

4.1 mg/L

Note 4

7

NOEC - Based on Mortality

2.5 mg/L

Note 4

NOEC - Based on Overall Endpoints

Pimephales promelas

Fathead Minnow

OECD 210

32 d

0.010 mg/L

Note 4

8

LOEC - Based on Overall Endpoints

>0.010 mg/L

Note 4

EC50 - Based on Activated Sludge Respiration Inhibition

-

-

OECD 209

3 h

>100 mg/L

Note 3

9

NOEC - Based on Activated Sludge Respiration Inhibition

10 mg/L

Note 3




PNEC (Predicted No Effect Concentration)

Long term tests have been undertaken for species from three trophic levels, based on internationally accepted guidelines. Therefore, the PNEC is based on results from the assessment of the most sensitive species, fathead minnow (Pimephales promelas), NOEC = 10 µg/L and an assessment factor of 10 is applied, in accordance with ECHA guidance (Ref.  10).


PNEC = 10/10 μg/L = 1.0 μg/L


Environmental risk classification (PEC/PNEC ratio)


0.000061 μg/L / 1.0 μg/L = 0.000061 i.e. PEC/PNEC < 0.1 which justifies the phrase “Use of vandetanib has been considered to result in insignificant environmental risk.”


In Swedish: ”Användning av vandetanib har bedömts medföra försumbar risk för miljöpåverkan.

” under the heading ”Miljörisk”.


Environmental Fate Data


Endpoint

Method

Test Substance Concentration

Time

Result

Reference

Percentage Biodegradation

OECD 301F

10 mg/L

Note 3

28 d

<5 %

11

Soil Dissipation Rate

OECD 307

Sandy Loam Soil

119 d

Bound rapidly to soil, no degradation observed







12

Clay Soil

119 d

Bound rapidly to soil, no degradation observed

Percentage Mineralisation

OECD 308

HOM sediment (aerobic system)

98 d

<1 %












13

LOM sediment

(aerobic system)

<1 %

HOM sediment

(anaerobic system)

<1 %

LOM sediment

(anaerobic system)

<1 %

Dissipation Half lives from water*

HOM and LOM sediment (aerobic system)

-

<11 days

HOM and LOM sediment

(anaerobic system)

-

<11 days

Sewage Adsorption Coefficient

OPPTS 835.1110

0.250 mg/L

-

Kd = 8400

14

HOM = High Organic Matter, LOM = Low Organic Matter

*Only a small % of the Applied Radioactivity could be extracted from the sediment. Not possible to determine total system half-life.



Biodegradation

Vandetanib is not readily biodegradable in accordance to the OECD 301F. There is evidence that the substance will strongly bind to sludge and sediment in the aquatic environment.


In the OECD 308 study, radiolabelled test substance was dosed into the overlying water and the subsequent dissipation from the water phase, and partitioning and/or degradation in the sediment, phase was observed over a 98 day test period. Aerobic and anaerobic test systems containing water and sediment differing in organic carbon content were used in the study. Evidence from the study shows that vandetanib is likely to rapidly dissipate from the aqueous phase and partition into the solid phase in both aerobic and anaerobic systems. By Day 11, in both high organic matter (HOM) and low organic matter (LOM) of the aerobic and anaerobic test systems, <2% of the applied radioactivity (AR) remained in the overlying waters with the rest partitioning into the sediment. Despite extraction using Ethanol, Tetrahydrofuran (THF) and Soluene, only a small proportion of the AR was extractable from the sediment (<17% aerobic test system; <24% anaerobic test system). Non extractable residues accounted for >74% of the AR at Day 98 so it was not possible to establish degradation half-lives in the sediment and the total system, or to determine whether primary degradation had taken place.


No degradation products or extractable metabolites with concentrations of > 10% of the AR were detected during the study.


No significant mineralization or volatile components were detected throughout the study.


Based on the data above, vandetanib is not predicted to be readily biodegradable during wastewater treatment, and therefore the phrase "Vandetanib is potentially persistent" is assigned.


In Swedish: “Vandetanib är potentiellt persistent” under the heading “Nedbrytning”.


Physical Chemistry Data

Endpoint

Method

Test Conditions

Result

Reference

Solubility Water

OECD 105

30°C followed by 24 h @ 20°C

≥3200 mg/L @ pH 5

260 mg/L @ pH 7

1.2 mg/L @ pH 9

15

Partition Coefficient Octanol Water

OECD 107

-

LogDow = -0.684 @ pH 3, 20°C

LogDow = 2.21 @ pH 7, 20°C

LogDow >3.90 @ pH 11, 20°C

16

Percentage Hydrolysis

OECD 111

-

<10 % @ pH 4, 7 & 9, 50°C

17

Hydrolysis Half-life

≥1 yr (Estimated)

Dissociation Constant

OECD 112

-

pKa = 5.14 (NH Group)

18

Dissociation Constant

Estimated using ACD Software for N with adjoining methyl group

-

pKa = 9.32

Soil Adsorption Coefficient

OECD 121

-

Log Koc = 2.1 @ pH 1.0

Log Koc > 5.0 @ pH 11.5

19

Note 1: Results are expressed as mean measured concentrations

Note 2: The relevant endpoints measured were emergence, survival and growth

Note 3: Results are expressed as nominal concentrations

Note 4: Concentrations were confirmed by analysis, and results expressed as nominal



Bioaccumulation

Log P = < 4 at pH 7.


Vandetanib has no significant bioaccumulation potential, as indicated by the log P. Therefore the "statement" Vandetanib has low potential for bioaccumulation’ is assigned.


In Swedish: “Vandetanib har låg potential att bioackumuleras” under the heading “Bioackumulering”.


References

  1. [ECHA] European Chemicals Agency. February 2016. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.16: Environmental exposure assessment (version 3.0) http://echa.europa.eu/documents/10162/13632/information_requirements_r16_en.pdf

  2. Investigator’s Brochure Vandetanib (Zactima. ZD6474), Section 5 Effects in humans. January 2007.


  3. ZD674: Toxicity to the green alga Selenastrum capricornutum.

    Brixham Environmental Laboratory, Report BL7990. Feb 2005.


  4. ZD6474: Acute toxicity to Daphnia magna.

    Brixham Environmental Laboratory, Report BL7991. Feb 2005.


  5. ZD6474. Chronic Toxicity to Daphnia magna.

    Brixham Environmental Laboratory, Report BL8340. July 2007.


  6. [14C]ZD6474: Effects in sediment on emerging midge, Chironomus riparius.

    Brixham Environmental Laboratory, Report BL8389. Dec 2006.


  7. ZD6474Acute toxicity to rainbow trout (Oncorhynchus mykiss).

    Brixham Environmental Laboratory, Report BL7992. Feb 2005.


  8. ZD6474: Determination of effects of the Early –Life Stage of the fathead minnow (Pimephales promelas). Brixham Environmental Laboratory, Report BL8374. October 2006.


  9. ZD6474: Effect on the respiration rate of activated sludge.

    Brixham Environmental Laboratory, Report BL7950. January 2005.


  10. ECHA, European Chemicals Agency. May 2008. Guidance on Information Requirements and Chemical Safety Assessment. Chapter R.10: Characterisation of dose [concentration]-response for environment http://echa.europa.eu/documents/10162/13632/information_requirements_r10_en.pdf

  11. ZD6474: Determination of 28 day ready biodegradability.

    Brixham Environmental Laboratory, Report BL8023. Feb 2005.


  12. ZD6474: Transformation in soil. Brixham Environmental Laboratory, Report No. BL8676/B. December 2008.


  13. ZD6474: Aerobic and anaerobic transformation in aquatic sediment systems. Brixham Environmental Laboratory, Report BL8312. January 2007.


  14. ZD6474: Adsorption to Sewage Sludge. Brixham Environmental Laboratory, Report BL8348. April 2007.


  15. ZD6474: Water solubility. Brixham Environmental Laboratory, Report BL8075. July 2005.


  16. ZD6474: Determination of n-octanol/water partition coefficient. Report No. BL8076/B. Brixham Environmental Laboratory, Brixham, UK. July 2005.


  17. ZD6474: Hydrolysis as a function of pH. Brixham Environmental Laboratory, Report BL8077. June 2005.


  18. BL8055. ZD6474: Determination of dissociation constants in water.

    Safepharm Laboratories. March 2005.


  19. BL7993. ZD6474: Estimation of the adsorption coefficient on soil. (HPLC method).

    Brixham Environmental Laboratory. June 2005.

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